[Conjugate of podophyllotoxin with chlorambucil: synthesis, biological testing and molecular modeling]

In the present work we have studied a novel conjugate of the DNA alkylating agent chlorambucil with podophyllotoxin, a ligand of the colchicine binding site in tubulin. The target compound was obtained by Steglich esterification of podophyllotoxin with the percentage yield of 41%. Results of biotesting carried out on the carcinoma A549 cell line revealed that at a concentration of 2 μM the conjugate caused full depolymerization of microtubules without any other effect on free tubulin. The conjugate inhibited proliferation (IC50=135±30 nM) and growth (EC50=240±30 nM) of A549 cells. The data of computer molecular docking of the novel compound into the 3D model of the colchicine binding site in α,β-tubulin and molecular dynamics modelling allowed to explain the observed difference in effects of chlorambucil-podophyllotoxin and chlorambucil-colchicine conjugates on microtubules.